{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,11,5]],"date-time":"2026-11-05T02:05:12Z","timestamp":1793844312602,"version":"4.6.1"},"reference-count":52,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"744","content-domain":{"domain":["www.science.org"],"crossmark-restriction":true},"short-container-title":["Sci. Transl. Med."],"published-print":{"date-parts":[[2024,4,24]]},"abstract":"<jats:p>The Fontan operation is the current standard of care for single-ventricle congenital heart disease. Individuals with a Fontan circulation (FC) exhibit central venous hypertension and face life-threatening complications of hepatic fibrosis, known as Fontan-associated liver disease (FALD). The fundamental biology and mechanisms of FALD are little understood. Here, we generated a transcriptomic and epigenomic atlas of human FALD at single-cell resolution using multiomic snRNA-ATAC-seq. We found profound cell type\u2013specific transcriptomic and epigenomic changes in FC livers. Central hepatocytes (cHep) exhibited the most substantial changes, featuring profound metabolic reprogramming. These cHep changes preceded substantial activation of hepatic stellate cells and liver fibrosis, suggesting cHep as a potential first \u201cresponder\u201d in the pathogenesis of FALD. We also identified a network of ligand-receptor pairs that transmit signals from cHep to hepatic stellate cells, which may promote their activation and liver fibrosis. We further experimentally demonstrated that activins A and B promote fibrotic activation in vitro and identified mechanisms of activin A\u2019s transcriptional activation in FALD. Together, our single-cell transcriptomic and epigenomic atlas revealed mechanistic insights into the pathogenesis of FALD and may aid identification of potential therapeutic targets.<\/jats:p>","DOI":"10.1126\/scitranslmed.adk6213","type":"journal-article","created":{"date-parts":[[2024,4,24]],"date-time":"2024-04-24T13:58:10Z","timestamp":1713967090000},"update-policy":"https:\/\/doi.org\/10.34133\/aaas_crossmark","source":"Crossref","is-referenced-by-count":27,"title":["Single-cell multiomics guided mechanistic understanding of Fontan-associated liver disease"],"prefix":"10.1126","volume":"16","author":[{"ORCID":"https:\/\/orcid.org\/0000-0003-2422-1652","authenticated-orcid":true,"given":"Po","family":"Hu","sequence":"first","affiliation":[{"name":"Center for Mitochondrial and Epigenomic Medicine, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."},{"name":"Cardiovascular Institute, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."},{"name":"Department of Pathology and Laboratory Medicine, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."},{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8625-6565","authenticated-orcid":true,"given":"Jack","family":"Rychik","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Juanjuan","family":"Zhao","sequence":"additional","affiliation":[{"name":"Center for Mitochondrial and Epigenomic Medicine, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."},{"name":"Cardiovascular Institute, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."},{"name":"Department of Pathology and Laboratory Medicine, 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USA."},{"name":"Cardiovascular Institute, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."},{"name":"Department of Pathology and Laboratory Medicine, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."},{"name":"Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Wenbao","family":"Yu","sequence":"additional","affiliation":[{"name":"Center for Childhood Cancer Research, Children\u2019s Hospital of Philadelphia, Philadelphia, PA 19104, USA."},{"name":"Department of Pediatrics, University of Pennsylvania, Philadelphia, PA 19104, USA."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-1173-4558","authenticated-orcid":true,"given":"Elizabeth B.","family":"Rand","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Children\u2019s Hospital of Philadelphia, 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